Arylsulfonamide ethers, and methods of use thereof

Abstract

The novel arylsulfonamide ether compounds, pharmaceutical compositions and uses thereof as inhibitors of interleukin-1β converting enzyme and other cysteine proteases in the ICE family are described. In one embodiment, the compound is described by the generalized structure: and pharmaceutically acceptable salts, esters, amides, and prodrugs thereof. In addition, methods of treating stroke, inflammatory diseases, septic shock, repurfusion injury, Alzheimer's disease, and shigellosis, using a compound of the invention or a pharmaceutical composition thereof, are described.

1. A compound represented by generalized structure 1: 
                 
 
       wherein
 Z represents carboxylate, alkoxycarbonyl, or aryloxycarbonyl;  
 G represents formyl or —CN; or  
 Z, G, and R, together with the carbon atoms in the generalized structure 1 to which they are attached, form a radical of the formula: 
                 
 
 J represents optionally substituted benzimidazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, adamantyl, azabenzimidazolyl, or indazolyl;  
 X represents (C(R) 2 ) f , or (C(R) 2 ) f (C(R) 2 );  
 R represents independently for each occurrence H or alkyl;  
 R 2  is absent or present 1, 2, or 3 times;  
 R 2  represents independently for each occurrence alkyl, alkenyl, alkynyl, halogen, formyl, acyl, carboxylate, alkoxycarbonyl, aryloxycarbonyl, carboxamido, alkylamino, acylamino, hydroxyl, alkoxyl, acyloxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, (alkylamino)alkyl, alkylthio, mercapto, mercaptoalkyl, (alkylthio)alkyl, carbamoyl, ureido, thioureido, sulfonyl, sulfonate, sulfonamido, sulfonylamino, or sulfonyloxy;  
 R 3  represents hydrogen, alkoxyl, amino, alkylamino, dialkylamino, (aminoalkyl)amino, ((alkylamino)alkyl)amino, ((dialkylamino)alkyl)amino, acylamino, (aminoacyl)amino, ((alkylamino)acyl)amino, ((dialkylamino)acyl)amino, (heterocyclyl)acylamino, carboxamido, (aminoalkyl)carboxamido, (alkylamino)alkyl)carboxamido, (dialkylamino)alkyl)carboxamido, sulfonylamino, urea, thiourea, —C(O)N(R)N(R) 2 , —C(O)N(R)C(R) 2 CO 2 H, or —C(O)N(R)C(R) 2 C(O)N(R) 2 ;  
 f represents 1, 2, or 3; and  
 the stereochemical configuration at any stereocenter of a compound represented by 1 may be R, S, or a mixture of these configurations,  
 
       and the pharmaceutically acceptable salts, thereof. 
     
     
       2. The compound of  claim 1 , wherein Z represents carboxylate. 
     
     
       3. The compound of  claim 1 , wherein G represents formyl. 
     
     
       4. The compound of  claim 1 , wherein X represents (CH(R)) f . 
     
     
       5. The compound of  claim 1 , wherein R 2  is absent. 
     
     
       6. The compound of  claim 1 , wherein f is 2. 
     
     
       7. The compound of  claim 1 , wherein Z represents carboxylate; and G represents formyl. 
     
     
       8. The compound of  claim 1 , wherein Z represents carboxylate; G represents formyl; and X represents (CH(R)) f . 
     
     
       9. The compound of  claim 1 , wherein Z represents carboxylate; G represents formyl; and R 2  is absent. 
     
     
       10. The compound of  claim 1 , wherein Z represents carboxylate; G represents formyl; and f is 2. 
     
     
       11. The compound of  claim 1 , wherein Z represents carboxylate; G represents formyl; X represents (CH(R)) f ; and R 2  is absent. 
     
     
       12. The compound of  claim 1 , wherein Z represents carboxylate; G represents formyl; X represents (CH(R)) f ; and f is 2. 
     
     
       13. The compound of  claim 1 , wherein Z represents carboxylate; G represents formyl; R 2  is absent; and f is 2. 
     
     
       14. The compound of  claim 1 , wherein Z represents carboxylate; G represents formyl; X represents (CH(R)) f ; R 2  is absent; and f is 2. 
     
     
       15. A compound represented by generalized structure 2: 
                 
 
       wherein
 Z represents carboxylate, alkoxycarbonyl, or aryloxycarbonyl;  
 G represents formyl or —CN; or  
 Z, G, and R, together with the carbon atoms in the generalized structure 2 to which they are attached, form a radical of the formula: 
                 
 
 J represents optionally substituted 1-, 4-, or 7-benzimidazolyl, 4-, or 5-quinolinyl, 4-isoquinolinyl, 5-tetrahydroquinolinyl, 1-adamantyl, 4-azabenzimidazol-3-yl, or 1-indazolyl;  
 R represents independently for each occurrence H or alkyl;  
 R 3  represents hydrogen, alkoxyl, amino, alkylamino, dialkylamino, (aminoalkyl)amino, ((alkylamino)alkyl)amino, ((dialkylamino)alkyl)amino, acylamino, (aminoacyl)amino, ((alkylamino)acyl)amino, ((dialkylamino)acyl)amino, (heterocyclyl)acylamino, carboxamido, (aminoalkyl)carboxamido, ((alkylamino)alkyl)carboxamido, ((dialkylamino)alkyl)carboxamido, sulfonylamino, urea, thiourea, —C(O)N(R)N(R) 2 , —C(O)N(R)C(R) 2 CO 2 H, or —C(O)N(R)C(R) 2 C(O)N(R) 2 ; and  
 
       the stereochemical configuration at any stereocenter of a compound represented by 2 may be R, S, or a mixture of these configurations, 
       and the pharmaceutically acceptable salts thereof. 
     
     
       16. The compound of  claim 15 , wherein R 3  is selected from the group consisting of: 
                 
                 
 
     
     
       17. The compound of  claim 15 , wherein J is selected from the group 
                 
                 
                 
                 
 
     
     
       18. The compound of  claim 16 , wherein J is selected from the group 
                 
                 
                 
                 
 
     
     
       19. The compound of  claim 17 , wherein Z represents carboxylate. 
     
     
       20. The compound of  claim 17 , wherein G represents formyl. 
     
     
       21. The compound of  claim 17 , wherein R represents independently for each occurrence hydrogen or methyl. 
     
     
       22. The compound of  claim 17 , wherein Z represents carboxylate; and G represents formyl. 
     
     
       23. The compound of  claim 17 , wherein Z represents carboxylate; G represents formyl; and R represents independently for each occurrence hydrogen or methyl. 
     
     
       24. The compound of  claim 1  or  15 , wherein said compound has an IC 50  less than 1 μM against an interleukin converting enzyme. 
     
     
       25. The compound of  claim 1  or  15 , wherein said compound has an IC 50  less than 500 nM against an interleukin converting enzyme. 
     
     
       26. The compound of  claim 1  or  15 , wherein said compound has an IC 50  less than 250 nM against an interleukin converting enzyme. 
     
     
       27. A pharaceutical composition comprising a compound of any of claims  1 - 14  and a pharmaceutically acceptable carrier thereof. 
     
     
       28. A pharmaceutical composition comprising a compound of any of claims  15 - 23  and a pharmaceutically acceptable carrier thereof. 
     
     
       29. A method of treating arthritis, comprising administrering to a patient having arthritis a therapeutically effective amount of a compound of  claim 1  or  15 .